Since the first recognition of AIDS as a clinical syndrome in 1981, remarkable progress has been made in defining the causative agent (HIV, or human immunodeficiency virus) and in characterizing its molecular and biological properties. Considerably less is known, however, about the basic pathogenetic mechanisms by which HIV induces persistent and fatal disease. Elucidation of the pathogenesis of HIV is essential for the development of effective preventive and treatment measures against the virus. We propose to establish a Program of Excellence for Basic Research on AIDS (PEBRA) whose programmatic theme and overall objective will be the elucidation of molecular mechanisms underlying HIV replication and pathogenesis. The Birmingham PEBRA will consist of a coordinated and multidisciplinary research effort involving seven projects, each of which will examine distinct viral and cellular processes involved in HIV replication and pathogenesis. Both HIV- 1 and HIV-2 will be studied. Project #1 will identify and characterize molecular determinants of HIV-2 pathogenicity and will define the role of novel HIV-2 gene products in regulating viral replication. Project #2 will define sites and primary amino acid sequence requirements for HIV-1 envelope precursor cleavage and will characterize the cellular enzymes involved in this critical processing event. Project #3 will define the function and structural biology of the HIV-2 envelope glycoprotein. Project #4 will identify and characterize HIV-1 viral proteins responsible for early replication events. Project #5 will examine the molecular and biologic consequences of HIV-1 infection of human astrocytes and will examine cellular and autocrine events that alter astrocyte and HIV gene expression. Project #6 will examine the biology of newly-discovered subpopulations of human CD4 lymphocytes which are distinguished by cell surface antigens and relative stage of activation and will define the replicative activity of HIV in the cells. In parallel, the project will also examine the structure, function, and expression of the avian CD4 molecule as a novel approach for defining the evolution of CD4. Project #7 will define the level and pattern of HIV-1 replication in vivo in naturally-infected adult and pediatric populations and will define and characterize molecular determinants of HIV-1 replication and virulence in field isolates of the virus. These studies will thus define at a molecular level biologic processes critical to viral replication and virulence and will relate this basic information to the elucidation of disease pathogenesis and strategies for treatment and prevention. In this program project, emphasis has been placed on the development of research directions that are unified by the programmatic objectives, that draw upon the strengths and expertise of the respective program leaders, and that represent novel approaches to the elucidation of basic mechanisms of viral pathogenesis.